1. Field of the Invention
The present invention is directed to compositions comprising tetrahydroindolone linked to arylpiperazines for the treatment of psychosis and psychosis related diseases including cognitive impairment.
2. Background
Psychiatric and neurologic disorders are among the most severe and chronic diseases and conditions. These disorders are also extremely difficult to treat effectively because of the multiplicity of the symptoms and etiologies. Although many alternative and combination drug therapies have been attempted and proposed, an effective treatment remains elusive. The current therapies have focused on either high selectivity for one pharmacological effect or broad non-selectivity to attempt multiple symptom relief. Drug therapies that have focused on high pharmacological selectivity have limited benefit for disorders with multiple causes and can worsen some symptoms. For example, selective antagonism of dopaminergic receptors for schizophrenia results in a worsening of negative symptoms and tardive dyskinesia. In contrast to selective drug therapy, drug therapies having broad non-selectivity can provide relief for more symptoms, yet they have more side effects. For instance, current antipyschotic drugs have adrenergic, cholinergic, and histaminergic receptor antagonist activity which are associated with deterioration of cognitive function and other side-effects such as orthostatic hypotension, dry mouth, blurred vision, constipation, and motor impairment. Regardless of drug therapy selectivity, cognitive decline is one main symptom that is not adequately treated in both current psychiatric and neurological therapies.
Therefore, there is a particular need for the development of compounds that have improved activity in treating psychiatric disorders having symptoms including reduced cognition and emotional control such as schizophrenia, schizoaffective disorders, anxiety and depression with agitation without the side-effects of the existing therapies. There is a further need for compounds that provide treatment or relief from symptoms associated with neurological diseases such as, Alzheimer""s disease, movement disorders, (such as Huntington""s disease and Parkinson""s disease), stroke pain and other neurodegenerative disorders, which can be genetic, spontaneous or iatrogenic. Additionally, there is a need for compounds that are neuroprotective, stimulate neuronal function, neuronal regeneration, neurogenesis and have fewer side effects.
Generally, the present invention relates to novel composite compounds having the general schematic structure, A}-L-{B, where A is a bicyclic ring structure such as tetrahydroindolone or a purine derivative, L is a hydrocarbyl chain, and B is an arylpiperazine or arylpiperazine derivative that are useful as pharmaceutical compositions for treating a wide range of psychiatric and neurological disorders.
Furthermore, these psychiatric and neurological disorders can be effectively treated without causing a deterioration of cognitive function or other major side effects. More particularly, the composite compounds of the present invention comprise tetrahydroindolones or purine derivatives linked to arylpiperazine structures.
Moreover, the composite compounds of the present invention can have other beneficial effects such as, but not limited to neuroprotective and neuroregenerative properties.
In accordance with the present invention, and as used herein, the following terms, when appearing alone or as part of a moiety including other atoms or groups, are defined with the following meanings, unless explicitly stated otherwise. In addition, all groups described herein can be optionally substituted unless such substitution is excluded. The term xe2x80x9calkyl,xe2x80x9d as used herein at all occurrences, refers to saturated aliphatic groups including straight-chain, branched-chain, and cyclic groups, all of which can be optionally substituted. Preferred alkyl groups contain 1 to 10 carbon atoms. Suitable alkyl groups include methyl, ethyl, and the like, and can be optionally substituted. The term xe2x80x9cheteroalkylxe2x80x9d as used herein at all occurrences refers to carbon-containing straight-chained, branch-chained and cyclic groups, all of which can be optionally substituted, containing at least one O, N or S heteroatoms. The term xe2x80x9cheteroalkenylxe2x80x9d as used herein at all occurrences refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chained, branch-chained and cyclic groups, all of which can be optionally substituted, containing at least one O, N or S heteroatoms. The term xe2x80x9calkenyl,xe2x80x9d as used herein at all occurrences, refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chain, branched-chain, and cyclic groups, all of which can be optionally substituted. Preferable alkenyl groups have 2 to 10 carbon atoms. The term xe2x80x9calkoxyxe2x80x9d refers to the ether xe2x80x94O-alkyl, where alkyl is defined as above. The term xe2x80x9carylxe2x80x9d refers to aromatic groups which have at least one ring having a conjugated xcfx80-electron system and includes carbocyclic aryl and biaryl, both of which can be optionally substituted. Preferred aryl groups have 6 to 10 carbon atoms. The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl and the like; these groups can be optionally substituted. The term xe2x80x9caralkenylxe2x80x9d refers to an alkenyl group substituted with an aryl group. The term xe2x80x9cheteroarylxe2x80x9d refers to carbon-containing 5-14 membered cyclic unsaturated radicals containing one, two, three, or four O, N, or S heteroatoms and having 6, 10, or 14 xcfx80-electrons delocalized in one or more rings, e.g., pyridine, oxazole, indole, thiazole, isoxazole, pyrazole, pyrrole, each of which can be optionally substituted as discussed above. The term xe2x80x9csulfonylxe2x80x9d refers to the group xe2x80x94S(O2)xe2x80x94. The term xe2x80x9calkanoylxe2x80x9d refers to the group xe2x80x94C(O)Rg, where Rg is alkyl. The term xe2x80x9caroylxe2x80x9d refers to the group xe2x80x94C(O)Rg, where Rg is aryl. Similar compound radicals involving a carbonyl group and other groups are defined by analogy. The term xe2x80x9caminocarbonylxe2x80x9d refers to the group xe2x80x94NHC(O)xe2x80x94. The term xe2x80x9coxycarbonylxe2x80x9d refers to the group xe2x80x94OC(O)xe2x80x94. The term xe2x80x9cheteroaralkylxe2x80x9d refers to an alkyl group substituted with a heteroaryl group. Similarly, the term xe2x80x9cheteroaralkenylxe2x80x9d refers to an alkenyl group substituted with a heteroaryl group. Where used herein, the term xe2x80x9clower,xe2x80x9d in reference to an alkyl or the alkyl portion of an another group including alkyl, is defined as a group containing one to ten carbon atoms, more typically one to six carbon atoms. The term xe2x80x9coptionally substitutedxe2x80x9d refers to one or more substituents that are typically lower alkyl, aryl, amino, hydroxy, lower alkoxy, aryloxy, lower alkylamino, arylamino, lower alkylthio, arylthio, or oxo, in some cases, other groups can be included, such as cyano, acetoxy, or halo. The term xe2x80x9chaloxe2x80x9d refers generally to fluoro, chloro, bromo, or iodo; more typically, xe2x80x9chaloxe2x80x9d refers to chloro.
In accordance with the present invention, and as used herein, the term xe2x80x9cderivativexe2x80x9d refers to a compound that is modified or partially substituted with another component. Additionally, the term xe2x80x9cderivativexe2x80x9d encompasses compounds that can be structurally similar but can have similar or different functions.
The composite compounds of the present invention have the general schematic structure, A}-L-{B, where A is a bicyclic ring structure such as tetrahydroindolone or a purine derivative, L is a hydrocarbyl chain, and B is an arylpiperazine or arylpiperazine derivative.
In one embodiment of the present invention, A is an 8-10 atom bicyclic moiety in which the five-aromatic membered ring has 1 to 2 nitrogen atoms, the bicyclic moiety having the structure of formula (I): 
where:
(a) formula I is bonded to a hydrocarbyl linker L;
(b) A2 is C or N;
(c) R3 is hydrogen, alkyl, aralky, heteroaralkyl, heteroalkyl, alkenyl, aralkenyl, heteroaralkenyl, heteroalkenyl, aryl, or heteroaryl;
(d) X4 is O, S or Nxe2x80x94OH;
(e) R5 is hydrogen, alkyl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, NH2, NHQ1, NQ1Q2, OH, OQ1, or SQ1, where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q1 and Q2 are present together and are alkyl, they can be taken together to form a 5- or 6-membered ring which can contain 1 other heteroatom which can be N, O, or S, of which the N can be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(f) R5xe2x80x2 is hydrogen unless R5 is alkyl, in which case R5xe2x80x2 is hydrogen or the same alkyl as R5;
(g) R5 and R5xe2x80x2 can be taken together as a double bond to C5 and can be O, S, NQ3, or C which can be substituted with one or two groups R5, where Q3 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(h) R6 is hydrogen, alkyl, aryl, heteroaryl;
(i) R6xe2x80x2 is hydrogen unless R6 is alkyl, in which case R6xe2x80x2 is hydrogen or the same alkyl as R6;
(j) n is 0 to 2.
As shown in Formula (I), the moiety A has a five, six, or seven-membered saturated ring fused to a five-membered aromatic ring. The five-membered aromatic ring can have one or two nitrogen atoms as indicated, but the five-membered aromatic ring always has a nitrogen atom at the 1-position. Typically, the five-membered aromatic ring has one nitrogen atom as in tetrahydroindolone. This nitrogen atom at the 1-position is covalently bonded to the linker L.
Typically A is a tetrahydroindolone moiety in which A2 is carbon and n is 1. The tetrahydroindolone moiety can be variously substituted.
In yet another embodiment of the present invention, A is a tetrahydroindolone moiety.
One example of a tetrahydroindolone moiety for the moiety A is a tetrahydroindolone moiety of Formula (II), below, in which: 
(1) Where X is H or CH2N(CH3)2;
(2) R5 is hydrogen, alkyl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, NH2, NHW1, NQ1Q2, OH, OQ1, or SQ1, where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, or heteroaroyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and where W1 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, or heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(3) R5xe2x80x2 is hydrogen;
(4) R6 is hydrogen, alkyl, aryl, heteroaryl;
(5) R6xe2x80x2 is hydrogen.
In one particularly preferred embodiment, R5, R5xe2x80x2, R6, and R6xe2x80x2, are all hydrogen. In this particularly preferred embodiment, the moiety A is an unsubstituted tetrahydroindolone moiety.
In addition to these examples of moieties suitable as moiety A1 other moieties can serve as moiety A1 including moieties with five or seven-membered saturated rings, and two nitrogen atoms in the five-membered aromatic ring or moieties with substituents at R3.
In another embodiment of the present invention, A is a substituted or unsubstituted 9-atom bicyclic moiety in which the five-membered ring has 1 to 3 nitrogen atoms, the bicyclic moiety having the structure of formula (III) 
where:
(a) if the bond between N1, and C6 is a single bond, then the bond between C6 and R6 is a double bond, R6 is O or S, and R1 is hydrogen, alkyl, aralkyl, cycloalkyl, or heteroaralkyl;
(b) if the bond between N1 and C6 is a double bond, then the bond between C6 and R6 is a single bond, R1 is not present, and R6 is hydrogen, halo, amino, OQ1, SQ1, NHNH2, NHOQ1, NQ1Q2, or NHQ1, where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q1 and Q2 are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which can contain 1 other heteroatom which can be N, O, or S, of which the N can be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(c) if the bond between C2 and N3 is a single bond, then the bond between C2 and R2 is a double bond, R2 is O or S, and R3 is hydrogen or alkyl;
(d) if the bond between C2 and N3 is a double bond, then the bond between C2 and R2 is a single bond, R3 is not present, and R2 is hydrogen, alkyl, aralkyl, cycloalkyl, heteroaralkyl, halo, amino, OQ1, SQ1, NHNH2, NHOQ1, NQ1Q2, or NHQ1, where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q1 and Q2 are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which can contain 1 other heteroatom which can be N, O, or S, of which the N can be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(e) A7 and A8 are C or N;
(i) if A7 and A8 are both C and the bond between A7 and A8 is a single bond, then the bond between A8 and R8 is two single bonds to two hydrogen atoms or is a double bond in which R8 is O or S and R7 is two hydrogen atoms;
(ii) if A7 and A8 are both C and the bond between A7 and A8 is a double bond, then R7 is hydrogen, the bond between A8 and R8 is a single bond and R8 is hydrogen, halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl;
(iii) if A7 and A8 are both N, then the bond between A7 and A8 is a double bond and R7 and R8 are not present;
(iv) if A7 is C and A8 is N, then the bond between A7 and A8 is a double bond, R7 is hydrogen, and R8 is not present;
(v) if A7 is N, A8 is C, and the bond between A7 and A8 is a double bond, then R7 is not present, the bond between A8 and R8 is a single bond, and R8 is hydrogen, halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl;
(vi) if A7 is N, A8 is C, and the bond between A7 and A8 is a single bond, then R7 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, the bond between A8 and R8 is a double bond, and R8 is O or S;
(f) N9 is bonded to linker L.
Particularly preferred purine moieties for the moiety A are described below.
One example of a purine moiety for the moiety A is a purine moiety of Formula (IV), below, in which: 
R1 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, heteroaralkyl, and
R2 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, heteroaralkyl, halo, amino, OQ1, SQ1, NHNH2, NHOQ1, NQ1Q2, or NHQ1, where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q1 and Q2 are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which can contain 1 other heteroatom which can be N, O, or S, of which the N can be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S.
The purine moiety of formula (IV) is a hypoxanthine or a guanine derivative.
In one particularly preferred embodiment, R1 is hydrogen and R2 is hydrogen.
In another preferred embodiment, R1 is hydrogen and R2 is amino.
In one particularly preferred embodiment, R1 is butyl and R2 is hydrogen.
In another preferred embodiment, R1 is benzyl and R2 is hydrogen.
In another preferred embodiment, R1 is dimethylaminoethyl and R2 is hydrogen.
In another preferred embodiment, R1 is cyclopentyl and R2 is hydrogen.
In another preferred embodiment, R1 is cyclohexylmethyl and R2 is hydrogen.
In another preferred embodiment, R1 is cyclopropylmethyl and R2 is hydrogen.
In another preferred embodiment, R1 is hydrogen and R2 is phenyl.
In another preferred embodiment, R1 is hydrogen and R2 is trifluoromethyl.
In another preferred embodiment, R1 is hydrogen and R2 is butyl.
In another preferred embodiment, R1 is butyl and R2 is butyl.
In another preferred embodiment, R1 is hydrogen and R2 is methyl.
In another preferred embodiment, R1 is hydrogen and R2 is phenylamino.
Another example of a purine moiety according to the present invention is the purine moiety of Formula (V), below, in which: 
R2 is selected from the group consisting of hydrogen, halo, amino, OQ3, SQ3, NHNH2, NHOQ3, NQ3Q4, or NHQ3, where Q3 and Q4 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q3 and Q4 are present together and are alkyl, they can be taken together to form a 5- or 6-membered ring which can contain one other heteroatom which can be N, O, or S, of which the N can be further substituted with Y3, where Y3 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S; and
R6 is selected from the group consisting of hydrogen, halo, amino, OQ5, SQ5, NHNH2, NHOQ5, NQ5Q6, or NHQ5, where Q5 and Q6 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q5 and Q6 are present together and are alkyl, they can be taken together to form a 5- or 6-membered ring which can contain one other heteroatom which can be N, O, or S, of which the N can be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S.
In one preferred example of this embodiment, R2 is hydrogen and R6 is xe2x80x94NH2 or xe2x80x94N(CH3)2.
In another preferred example of this embodiment, R2 is hydrogen and R6 is Cl.
In yet another preferred example of this embodiment, R2 is xe2x80x94NH2 and R6 is Cl.
Another example of a purine moiety according to the present invention is the purine moiety of Formula (VI), below, in which: 
R1 is hydrogen, alkyl, aralkyl, cycloalkyl, or heteroaralkyl.
R2 is O or S.
Preferably, R1 is hydrogen.
The purine moiety of Formula (VI) is a xanthine or thioxanthine moiety.
In addition to these examples of moieties suitable as moiety A1 other moieties can serve as moiety A1 including moieties with one or three nitrogen atoms in the five-membered ring or moieties with substituents at R8.
Typically, for purine derivatives according to the present invention, A is a hypoxanthine moiety.
In one embodiment, the linker L is a hydrocarbyl moiety with the structurexe2x80x94(CH2)mxe2x80x94 wherein m is an integer from 1 to 6. A preferred linker has m equal to 2, 3 or 4.
In another embodiment, linker L is a phenyl or a benzyl linked to a hydrocarbyl chain by group Y where group Y is located on the meta or para positions of the aromatic ring. Group Y can be nothing such that the hydrocarbyl chain is directly linked to the phenyl group. Group Y can also be an ether, thioether, carbonyl, thiocarbonyl, carboxamido, aminocarbonyl, amino, oxycarbonylamino, aminocarbonyloxy, aminocarbonylamino, oxythiocarbonylamino, aminothiocarbonyloxy, aminothiocarbonylamino, aminosulfonyl, or sulfonamido group.
B is an arylpiperazine or derivative having the structure of formula (VII): 
where:
(a) R2 is hydrogen, alkyl, hydroxy, halo, alkoxy, cyano, methylthio;
(b) R3 is hydrogen, alkyl, hydroxy, methoxy, halo, alkoxy, trifluoromethyl, nitro, amino, aminocarbonyl, aminosulfonyl;
(c) R2 and R3 can be taken together to form a 5 or 6 member aromatic or non-aromatic ring, which can contain from 0 to 3 heteroatoms selected from the group of N, O, or S.
(d) n equals 1 or 2
In one embodiment, B is a m-trifluoromethylphenylpiperazinyl moiety: 
In another embodiment, B is a m-chlorophenylpiperazinyl moiety: 
In yet another embodiment, B is an o-methoxyphenylpiperazinyl moiety: 
In another embodiment, B is a piperazine ring or derivative linked to a 6-member heterocyclic ring containing 1 to 3 N, having the structural formula (VIII): 
Wherein n=1 or 2 and the 6-member heterocyclic ring (Het) can be 2-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl, or 2-triazinyl. The heterocyclic ring can also be substituted where R can be halo, alkyl, cyano, trifluoromethyl, alkoxy, amino, alkylamino, or dialkyamino.
In one embodiment, B is a 2-pyrimidylpiperazinyl moiety: 
In another embodiment, B is a 1-pyrimidin-2-yl-[1,4]diazepane moiety: 
In yet another embodiment, B is a piperazine ring or derivative linked to a bicyclic moiety having the structural formula (IX): 
where:
(a) A1 is N, O, or S, and when it is N, it can be further substituted with Z, which is alkyl, aralkyl, heteroaralky, or heteroalkyl.
(b) A2 is C or N;
(c) and n is 1 or 2
(d) R is hydrogen, alkyl, NH2, NHQ1, NQ1Q2, OH, OQ1, SQ1, halo, nitro, cyano, or trifluoromethyl where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q1 and Q2 are present together and are alkyl, they can be taken together to form a 5- or 6-membered ring which can contain 1 other heteroatom which can be N, O, or S, of which the N can be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S.
In another embodiment, B is piperazine ring or derivative linked to a bicyclic moiety having the structure (X) below: 
where:
(a) A1 is N, O, or S, and when it is N, it can be further substituted with Z, which in alkyl, aralkyl, heteroaralky, or heteroalkyl.
(b) A2 is C or N;
(c) and n is 1 or 2
(d) R is hydrogen, alkyl, NH2, NHQ1, NQ1Q2, OH, OQ1, SQ1, halo, nitro, cyano, or trifluoromethyl where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q1 and Q2 are present together and are alkyl, they can be taken together to form a 5- or 6-membered ring which may contain 1 other heteroatom which can be N, O, or S, of which the N may be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S.
In another embodiment, B is a piperazine ring or derivative linked to a bicyclic moiety having the structural formula (X): 
where:
(a) o is 1 to 3;
(b) n is 1 or 2; and
(c) R is hydrogen, alkyl, NH2, NHQ1, NQ1Q2, OH, OQ1, SQ1, nitro, cyano, trifluoromethyl, or halo where Q1 and Q2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q1 and Q2 are present together and are alkyl, they can be taken together to form a 5- or 6-membered ring which can contain 1 other heteroatom which can be N, O, or S, of which the N can be further substituted with Y2, where Y2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S.
Generally, any moiety A can be combined with any linker L and any moiety B to produce a composite compound according to the present invention. However, in one embodiment the composite compounds of the present invention include, but are not limited to, the following structure: 
(a) wherein L is xe2x80x94(CH2)mxe2x80x94 wherein m is an integer from 1 to 6;
(b) R1 is: 
and R2 and R3 are the same or independently hydrogen, alkyl, hydroxy, methoxy, halo, alkoxy, trifluoromethyl, nitro, amino, aminocarbonyl, or aminosulfonyl.
More specifically, the composite compounds of the present invention include, but are not limed to:
(1) 1-{2-[4-(3-Trifluoromethylphenyl)piperazine-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one (NEO-359) 
(2) 1-{3-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one (NEO-356) 
(3) 1-{3-[4-(3-Chlorophenyl)piperazine-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one (NEO-363) 
(4) 1-{3-[4-(2-Methoxyphenyl)piperazine-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one (NEO-370) 
(5) 1-{3-[4-(2-Pyrimidyl)piperazine-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one (NEO-381) 
(6) 1-{2-[4-(3-Chloro-phenyl)-piperazin-1-yl]-ethyl}-1,5,6,7-tetrahydroindol-4-one (NEO-376) 
(7) 1-{4-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-butyl}-1,5,6,7-tetrahydroindol-4-one (NEO-392) 
(8) 1-{2-[4-(2-Methoxyphenyl)-piperazin-1-yl]-ethyl}-1,5,6,7-tetrahydroindol-4-one (NEO-377) 
Other examples of the composite compounds of the present invention include, but are not limited to:
(9) 9-{3-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]propyl}-1,9-dihydropurin-6-one 
(10) 6-Chloro-9-{3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl}-9H-purine 
(11) 1-{3-[4-(1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-propyl}-1,5,6,7-tetrahdro-indol-4-one 
(12) 1-[3-(4-Pyrimidin-2-yl-[1,4]diazepan-1-yl)-propyl]-1,5,6,7-tetrahydro-indol -4-one 
(13) 1-{3-[4-(3-Chloro-phenyl)-piperazin-1-yl]-propyl}-3-dimethylaminomethyl-1,5,6,7-tetrahydro-indol-4-one 
(14) 1-{3-[4-(1,2,3,4,-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-propyl}-1,5,6,7-tetrahydro-indol-4-one 
15) 1-[3-(4-Benzothiazol-2-ylpiperazin-1-yl)propyl]-1,5,6,7-tetrahydroindol-4-one 
(16) 1-[3-(4-Benzoxazol-2-ylpiperazin-1-yl)propyl]-1,5,6,7-tetrahydroindol-4-one 
According to the present invention, a tetrahydroindolone or purine derivative linked to moiety B is referred to as a xe2x80x9ccomposite compound.xe2x80x9d According to the present invention, moiety B has a biological, physiological, or pharmacological function, but it is not required that moiety B of the composite compound have a biological, physiological, or pharmacological function. The moiety B can serve as a carrier to improve bioavailability or to optimize the physical characteristics of the molecule without having a separate biological, physiological function, or pharmacological function.
Typically, the composite compound has a logP of from about 1 to about 4 to enhance bioavailability and central nervous system (CNS) penetration. Using this guideline, one of ordinary skill in the art can choose the appropriate moieties B for a particular moiety A in order to ensure the bioavailability and CNS penetration of the composite compound of present invention. For example, if a highly hydrophobic moiety A is chosen, with particularly hydrophobic substituents on the tetrahydroindolone or purine moiety, then a more hydrophilic moiety B can be used.
A number of composite compounds according to the present invention are optically active, owing to the presence of chiral carbons or other centers of asymmetry. In cases where composite compounds of the present invention are optically active, all of the possible enantiomers or diastereoisomers are included unless otherwise indicated despite possible differences in activity.
In general, composite compounds that are within the scope of the present invention also include salts and prodrug esters of these derivatives. It is well known that organic compounds, including substituted tetrahydroindolones, purines, arylpiperazines and other components of these composite compounds, have multiple groups that can accept or donate protons, depending upon the pH of the solution in which they are present. These groups include carboxyl groups, hydroxyl groups, amino groups, sulfonic acid groups, and other groups known to be involved in acid-base reactions. The recitation of a composite compound includes such salt forms as occur at physiological pH or at the pH of a pharmaceutical composition unless specifically excluded.
Similarly, prodrug esters can be formed by reaction of either a carboxyl or a hydroxyl group on the composite compound with either an acid or an alcohol to form an ester. Typically, the acid or alcohol includes a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. These groups can be substituted with substituents such as hydroxy, halo, or other substituents. Such prodrugs are well known in the art and need not be described further here. The prodrug is converted into the active compound by hydrolysis of the ester linkage, typically by intracellular enzymes. Other suitable groups that can be used to form prodrug esters are well known in the art.
Another aspect of the present invention is methods of use of the composite compounds described above. The therapeutic effects of the composite compounds of the present invention are achieved by the effects mediated by multiple receptors. That is, by providing multiple pharmacophores having different receptor activities, the present invention is able to achieve therapeutic benefits without adverse side effects. For example, composite compounds with the arylpiperazine component have serotonin (5-HT) and dopamine activity. In particular, the arylpiperazine component of the composite molecules will have 5-HT1, and specifically 5TH1A receptor agonist activity, with or without antagonism at 5-HT2 and D2, D3, and D4 dopamine receptors. Accordingly, composite compounds with all of these activities will be useful in treating schizophrenia, schizoaffective disorders, depression with agitation, and Huntington""s disease. These compounds will have fewer side-effects compared to current antipsychotics due to a lack of adrenergic, cholinergic, and histaminergic receptor antagonist activity. Other composite compounds from this series have 5-HT1A receptor agonist activity and with less selective activity at other receptors. These will be useful as antidepressants, anxiolytics, neuroprotectants and antiemetics.
Additionally, the tetrahydroindolone or purine derivative component of the composite compound is a pharmacophore having GABA activity. As those skilled in the art will appreciate, GABA receptors are highly localized in the hippocampal region of the brain which is associated with memory. GABA receptors may also be involved in psychosis. Accordingly, it is assumed that pharmacophores, such as tetrahydroindolone or purine derivatives, having GABA activity will improve cognitive function and enhance the therapeutic properties of the arylpiperazine moiety. GABA activity alone will be useful for improving cognition in patients.
An additional aspect of a method of use of composite compounds according to the present invention is a method of stimulating neuronal function such as improved cognition, involving neurogenesis, neuronal regeneration or axo-dendritic complexity in the central and peripheral nervous systems comprising the step of administering an effective amount of a composite compound according to the present invention to the mammal.
An additional aspect of a method of use of composite compounds according to the present invention is a method of stimulating neuronal function involving mechanism associated with neuroprotection in the central or peripheral nervous system of a mammal comprising the step of administering an effective amount of the described composite molecules according to the present invention to the mammal.
Methods for synthesis of purine and tetrahydroindolone derivatives according to the present invention are modified from those described, for example, in U.S. Pat. No. 5,091,432 to Glasky, incorporated herein by this reference. Generally, the tetrahydroindolone moiety is substituted with a linker which in turn is linked to the moiety B that completes the molecule as described above. This route comprises, in either order, the steps of: (1) synthesizing an appropriately substituted tetrahydroindolone moiety linked to an aliphatic linker in which the linker is terminated with a halogen; (2) reacting the halogen intermediate with the arylpiperazine to produce the final product. A similar route can be used for synthesis of purine derivatives according to the present invention using an appropriately substituted purine moiety as a starting material.
The length of the aliphatic linker covalently bound to the tetrahydroindolone or purine moiety can be varied to change the distance between the tetrahydroindolone or purine moiety and the moiety B in the composite compound of the present invention.
Composite compounds of the present invention incorporating an aryl piperazinyl moiety can be synthesized by a dihalide substitution reaction. Suitable substitution reactions are described, e.g., in M. B. Smith and J. March, xe2x80x9cMarch""s Advanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d (5th ed., Wiley-Interscience, New York, 2001).
Another reaction that can be used to functionalize tetrahydroindolones or purines is the Mitsunobu reaction. The Mitsunobu reaction is a highly versatile method for the introduction of widely varying functionality upon the tetrahydroindolone or purine moiety, because of the wide assortment of primary alcohols that are commercially available for use in this reaction.
Alternatively, in those embodiments where the composite compounds of the present invention include a purine moiety, the purine ring can be formed in stages, with the attachment of the linker and the moiety B occurring before the closure of the purine ring. This route involves: (1) the formation of aminocyanacetamide; (2) the reaction of aminocyanacetamide with triethyl orthoformate and acetonitrile to form an amidoester derivative of aminocyanacetamide; (3) the formation of a compound having a reactive amino group on a hydrocarbyl moiety, the hydrocarbyl moiety being linked to the moiety B; (4) the reaction of the amidoester with the compound having the reactive amino group on the hydrocarbyl moiety; (5) formation of the six-membered heterocyclic ring of the purine moiety; and (6) hydrolysis of the protecting group, if present, to form the final product.
Additionally, where the composite compounds of the present invention include a purine moiety, in one alternative, the step of the formation of the six-membered heterocyclic ring of the purine moiety can be performed by methods analogous to the ring closure of Yamazaki (A. Yamazaki et al., xe2x80x9cSynthesis of Guanosine and Its Derivatives from 5-Amino-1-xcex2-D-Ribofuranosyl-4-Imidazolecarboxamide I. Ring Closure with Benzoyl Isothiocyanate,xe2x80x9d J. Org. Chem. 32: 1825-1828 (1967)) or alternatively, by the method of Clausen (B. Alhede et al., xe2x80x9cA Simple and Efficient Synthesis of 9-Substituted Guanines. Cyclodesulfurization of 1-Substituted 5-[(Thiocarbamoyl)amino]imidazole-4-Carboxamides Under Aqueous Basic Conditions,xe2x80x9d J. Org. Chem. 56: 2139-2143 (1991)) involving catalysis by a heavy metal salt such as Cu2+, Ag+, or Hg2+ in aqueous NaOH, or, alternatively, by S-oxidation with hydrogen peroxide or sodium perborate in aqueous sodium hydroxide.